tbuckley/cabot-search huggingface dataset:
Abstract 15036: Suppression-Replacement Gene Therapy for <i>CALM1</i> -Mediated Long QT Syndrome
Authors: Kathryn E Tobert, Samantha K Hamrick, Martina Gluscevic, David J Tester, CS John Kim, Michael J Ackerman
Journal: Circulation (2022)

Introduction: Calmodulin (CaM)-mediated long QT syndrome (CaM-LQTS) is a genetic arrhythmia disorder characterized by a high prevalence of life-threatening ventricular arrhythmias occurring very early in life, frequent T-wave alternans, markedly prolonged QT intervals (QTc &gt; 600 ms), and intermittent 2:1 AV block. Three distinct genes ( CALM1 , CALM2 , and CALM3 ) all encode for the identical CaM protein. Conventional LQTS pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with CaM-LQTS. Here, we developed a CALM1 “ suppression-replacement (SupRep)” gene therapy with the goal of rescuing the prolonged cardiac action potential duration (APD) and increased Ca 2+ amplitude (ΔF/F0) in patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a patient with CALM1 -mediated LQTS. Methods: Custom designed CALM1 -targeting shRNAs were tested for knockdown efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep CALM1 gene therapy was created by cloning into a single construct a custom-designed CALM1 shRNA that produces knockdown (suppression) and a “shRNA-immune” (shIMM) CALM1 cDNA (replacement). Patient-specific CALM1-F142L iPSC-CMs were generated from a patient with severe LQTS (QTc = 515 ms). FluoVolt voltage-sensing dye was used to measure the APD at 90% repolarization (APD 90 ). Calcium transient amplitude was measured using Fluo-4 indicator. Results: Overall, 6 unique candidate CALM1 -targeting shRNAs were tested for knockdown efficiency in a transient transfection CALM1 over-expression TSA201 cell system. One candidate shRNA had an 80% knockdown efficiency of CALM1. Following transfection with CALM1 -SupRep gene therapy, the APD 90 was significantly decreased in F142L iPSC-CMs compared to untreated cells (F142L: 665 ± 9 ms [n=40] vs F142L + SupRep: 353 ± 9 ms [n=20], p&lt;0.0001). Ca 2+ amplitude was significantly decreased following SupRep transfection when compared to untreated cells (0.99 ± 0.04 vs 0.8 ± 0.06, p=0.02). Conclusions: Here, we provide the first proof-of-principle SupRep gene therapy for CALM1-mediated LQTS. CALM1 -SupRep gene therapy shortened significantly the pathologically prolonged APD 90 in CALM1 -F142L patient-derived iPSC-CMs.
Abstract 13226: Low-Carbohydrate Diets and Risk of Type 2 Diabetes in U.S. Men and Women
Authors: Yeli Wang, Yang Hu, Yi Wan, Eric B Rimm, Frank B Hu, Qi Sun
Journal: Circulation (2022)

Introduction: Evidence regarding associations between overall low-carbohydrate diets (LCDs) and the risk of developing type 2 diabetes (T2D) remains to be mixed. In the current analysis, we aimed to prospectively assess associations of various LCDs that emphasize different quality of protein, fat, and carbohydrate with T2D risk in U.S. men and women. Methods: A prospective cohort study was conducted in 203,541 men and women participating in the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study who were free of T2D, cardiovascular disease, and cancer at baseline and were followed for up to &gt;30 years. Five LCD scores based on sources of protein, fat, and carbohydrate differentiated by their qualities were derived every four years based on dietary assessments by a validated food frequency questionnaire. Results: During 5,095,048 person-years of follow-up, 19,675 T2D cases were documented. In the multivariable model, a higher overall LCD score was associated with higher T2D risk in a dose-response manner: the hazard ratio (HR) comparing highest vs. lowest quintile was 1.28 (95% confidence interval: 1.22-1.34; P -trend &lt;0.001). A vegetable-based LCD score that emphasizes vegetable protein and fat intake was associated with 6% lower T2D risk (0.94 [0.90-0.98; P -trend =0.003]), and a healthy LCD score that further de-emphasizes refined carbohydrate intake was associated with 15% lower T2D risk (0.85 [0.81-0.89; P -trend &lt;0.001]). In contrast, LCD scores emphasizing high animal protein and fat intake were associated with higher T2D risk. The HRs (95% CIs) comparing extreme quintiles were 1.35 (1.29-1.42; P -trend &lt;0.001) for an overall animal-based LCD score and 1.39 (1.32-1.46; P -trend &lt;0.001) when such a score that further de-emphasizes whole grain intake. Conclusions: LCDs were not beneficial for the primary prevention of T2D unless they emphasize the quality of the macronutrient compositions.
The NLRP3 inflammasome and gut dysbiosis as a putative link between HIV-1 infection and ischemic stroke
Authors: Silvia Torices, Leah Daire, Sierra Simon, Luisa Mendoza, Destiny Daniels, Joelle-Ann Joseph, Nikolai Fattakhov, Oandy Naranjo, Timea Teglas, Michal Toborek
Journal: Trends in Neurosciences (2023)

HIV-associated comorbidities, such as ischemic stroke, are prevalent in people with HIV (PWH). Several studies both in animal models and humans have revealed an association between activation of the inflammasome in HIV-1 infection and stroke. The gut microbiota is an important component in controlling neuroinflammation in the CNS. It has also been proposed to be involved in the pathobiology of HIV-1 infection, and has been associated with an increase in activation of the inflammasome. In this review, we provide an overview of the microbiota-gut-inflammasome-brain axis, focusing on the NLRP3 inflammasome and dysregulation of the microbiome as risk factors that may contribute to the outcome of ischemic stroke and recovery in PWH. We also focus on the potential of targeting the NLRP3 inflammasome as a novel therapeutic approach for PWH who are at risk of developing cerebrovascular diseases.
Abstract 15019: Safe Implantation of Remote Pulmonary Artery Pressure Monitoring System (CARDIOMEMS) in a Pregnant Patient With Severe Heart Failure
Authors: Javaria Ahmad, Hajra Awwab, Brittin Thibodeaux, Lillian Faucheaux, Danielle Cooper, Perry Barrilleaux, Davis Lewis, Paari Dominic
Journal: Circulation (2022)

Introduction: Heart failure (HF) in pregnancy is associated with high maternal and neonatal mortality. Remote pulmonary artery pressure (PAP)-guided management of HF has been shown to reduce hospitalizations and mortality in HF patients. However, PAP monitoring systems (CardioMEMS) have not been implanted during pregnancy. We describe the first case of safe implantation of CarioMEMS in a pregnant patient with HF. Case report: A 38-year-old female with past medical history of non-ischemic cardiomyopathy with an ejection fraction of 15%, left ventricular thrombus, pulmonary hypertension, and atrial fibrillation was found to be 14 weeks pregnant by the obstetrician, and her HF medications were appropriately discontinued. The patient was continued on metoprolol, amlodipine, and enoxaparin and was advised to terminate the pregnancy due to high risk of maternal mortality, however, she decided against it. An interdisciplinary team of obstetricians and cardiologists managed the patient during her pregnancy. As the pregnancy progressed, the patient had multiple hospitalizations due to decompensated HF. To optimize her hemodynamic status and guide diuretic therapy, a decision to implant CardioMEMS was made after a risk-benefit discussion, at 23 weeks of gestation. A long wire and sheath were used from a femoral venous access to limit fluoroscopy. A right heart catheterization was performed, and cardiac filling pressures and output were measured. Minimal contrast (7.5 ml of iodixanol) was used to perform selective pulmonary artery angiography and the sensor was implanted according to manufacturer recommendations. Total fluoroscopic exposure during the procedure was 11.2 minutes (183 Gy-cm2). Patient’s diuresis and afterload reduction was adjusted based on PAP. Conclusion: Remote PAP monitoring system can be safely implanted in pregnant patients using limited contrast and fluoroscopic exposure to proactively manage heart failure.
Abstract 15072: Targeted Atrial Inhibition of Parasympathetic Signaling With GiGo Inhibitory Peptides Attenuates Electrical Remodeling and Development of Persistent Atrial Fibrillation in a Canine Model
Authors: Anna Pfenniger, Shin Yoo, David Johnson, Wenwei Zhang, Azaria Panni, Amy Burrell, Suman Mandava, Markus Rottmann, Rod S Passman, Bradley P Knight, Rishi Arora
Journal: Circulation (2022)

Background: While vagal contribution to paroxysmal atrial fibrillation (AF) is well demonstrated, a role for parasympathetic signaling in persistent AF is less clear. We have shown marked atrial parasympathetic hyperinnervation in a canine rapid atrial pacing (RAP) model of AF. However, the role of these new nerves in AF development is unknown. Hypothesis: RAP-induced parasympathetic hyperinnervation contributes to the onset and maintenance of AF, and a gene therapy approach inhibiting muscarinic M2 signaling (Gα i and Gα o - GiGo) in the atria can prevent persistent AF. Methods: Plasmids expressing GiGo inhibitory peptides (GiGo_ct) were injected in the atria of 7 dogs followed by electroporation to facilitate gene delivery. RAP was performed for up to 12 weeks. At terminal EP study, residual AF was recorded in the posterior left atrium (PLA), left atrial free wall (LAFW) and left atrial appendage (LAA). Regional atrial ERP was measured. Results: Controls developed ≥30 minutes of AF after a median of 4 days, and persistent AF (≥8 hours) after a median of 14 days. GiGo_ct delayed onset of AF of ≥30 minutes, and attenuated development of persistent AF. ERP was markedly shortened in the PLA and LAA of controls, and this was attenuated by GiGo_ct (p&lt;0.001). Residual AF was slower (lower dominant frequency; PLA 9.4±0.6Hz Vs 11.0±0.7Hz; LAFW 7.8±0.3Hz Vs 10.4±0.7Hz; LAA 8.9±0.6Hz Vs 9.9±0.5Hz p&lt;0.01), less fractionated (longer fractionation interval; PLA 70.0.4±5.2ms Vs 68.1±5.2ms; LAFW 98.8±4.1ms Vs 70.9±3.1ms; LAA 88.9±7.8ms Vs 80.3±2.0ms p&lt;0.01) and more organized (lower Shannon's entropy; p&lt;0.05). Conclusion: Newly sprouted atrial parasympathetic nerves play a functional role in development of persistent AF. Gene-based, selective M2 signaling inhibition by GiGo_ct attenuates electrical remodeling and prevents initiation and maintenance AF. Future optimization of gene therapy targeting autonomic remodeling may lead to novel, mechanism-guided treatments for AF.
Abstract 14988: Longitudinal Strain for Early Identification of Anthracycline-Induced Cardiomyopathy in Pediatrics
Authors: Ogochukwu Ezeoke, Nazia Husain, Jennifer L Reichek, Dana R Franklin, Jennifer Acevedo, Kae Watanabe
Journal: Circulation (2022)

Introduction: Anthracycline-induced cardiomyopathy (ACM) affects pediatric cancer survivors and echocardiogram (echo) surveillance is required. In adults, a decline in global longitudinal strain (LS) &gt;15% is a pre-clinical marker of ACM. There is utility in determining change in strain associated with pre-clinical ACM in pediatrics. Methods: We queried our institutional database to identify patients &lt;19 yo, with acute myeloid leukemia (AML), Ewing’s sarcoma or osteosarcoma, who received anthracyclines (1/1/2008 - 12/31/2020), and developed sub-acute or chronic ACM (LVEF &lt;55% greater than 30 days post anthracycline completion). Echo at baseline (time of cancer diagnosis) and pre-ACM (within 2 years of first documented LVEF &lt;55%) were compared for strain differences. Four-chamber LS, mid-chamber circumferential strain (CS) and left atrial strain (LAS) were analyzed using TomTec software. Results: Twenty-two patients were eligible for analysis from 428 meeting inclusion criteria (Figure 1). Demographics are shown in Table 1. There was a significant decline in LS from baseline to pre-ACM echo (-20.7 +/-2.98 vs -18.2 +/-3.74; p=0.026) amounting to a mean absolute LS decline of 2.5% and relative decline of 12.4% from baseline. Differences in CS (25.15 +/-4.89 vs 23.44 +/-5.11; p=0.35), LAS (43.09 +/-10.48 vs 45.23 +/-13.43; p=0.54) and heart rate (99.55 +/-19.88 vs 90.24 +/-26.47; p=0.09) were not significant. Conclusions: A significant decrease in LS occurs following anthracyclines pre-dating the diagnosis of subacute or chronic ACM in children. Prospective research with established imaging protocols may validate the role of strain in surveillance for pediatric ACM.
Abstract 15002: Real-World Healthcare Resource Utilization Among US Patients With Atrial Fibrillation Receiving Dronedarone versus Ablation as 1st-Line Therapy
Authors: Stephen J Greene, Samantha Schilsky, Andrew W Roberts, Shaum M Kabadi, David MCKINDLEY, RON PREBLICK, Jason Rashkin, Reno Leeming, Renee Sajedian, Andrea M Russo
Journal: Circulation (2022)

Introduction: Catheter ablation is used increasingly as a 1st-line (1L) alternative to antiarrhythmic drugs (AAD) including dronedarone in patients with atrial fibrillation (AF). Healthcare resource utilization (HCRU)-related costs with dronedarone vs 1L ablation are unknown. Methods: We conducted a retrospective, observational cohort study using Optum Clinformatics Data Mart® from Jan 2012-Jan 2022 among US adults with AF and no prior rhythm control therapy who received new AAD therapy with dronedarone (index: date of incident dronedarone fill) vs those who received 1L ablation, or a non-dronedarone AAD followed by ablation within 3 mo (index: date of first recorded ablation or AAD). Patients were required to have ≥24 mo of pre-index data, and ≥3 mo follow-up. Patients in the 1L ablation cohort were propensity score matched 2:1 to the dronedarone cohort. Mean payer costs per patient per month (PPPM) during the 24-mo post-index period were calculated for total HCRU, inpatient visits, emergency room (ER) visits, outpatient physicians’ office visits, and all outpatient visits, and compared by zero-inflated negative binomial (ZINB) regression model. Results: Post-matching, the dronedarone (n=1440) and 1L ablation (n=2253) cohorts had similar baseline characteristics (mean age at index: 68.4 vs 67.7 years; male: 57.7% vs 59.3%; mean time from AF diagnosis to index: 80.2 vs 91.6 days; Charlson comorbidity index: 2.3 vs 2.2; CHADS2-VASc score: 3.4 vs 3.2). Mean PPPM costs were lower with dronedarone vs 1L ablation for all-cause total HCRU, inpatient visits, any outpatient visit, ER visit, and outpatient office visit (Table). ZINB analyses showed significant cost differences for all-cause total HCRU and any outpatient visit events. Conclusion: In patients with AF and no prior rhythm control therapy, 1L dronedarone was associated with lower total HCRU and outpatient visit costs during 24-mo follow-up vs 1L ablation; future studies will assess cost-effectiveness.
Abstract 14964: Photon Counting Computed Tomography for Aortic Valve Calcium Scoring in Contrast Enhanced Datasets of the Heart
Authors: Eva K Harmel, Franziska Braun, Franka Risch, Katharina Rippel, Christian Scheurig, Tamer Owais, Sebastien Elvinger, Evaldas Girdauskas, Thomas Kroencke, Philip W Raake, Florian Schwarz
Journal: Circulation (2022)

Introduction: The prognostic value of aortic valve calcification prior to transcatheter aortic valve replacement (TAVR) is well established. Its reliable quantification requires a non-contrast computed tomography (CT) of the heart (‘true non contrast’, TNC) which in this cohort is not regularly performed at all centers. Photon Counting Detector CT (PCD-CT) permits the routine derivation of ‘virtual non-contrast’ (VNC) and ‘virtual non-iodine’ (VNI) series from CT Angiography (CTA) acquisitions due to its intrinsic spectral sensitivity. These might render separate non-contrast acquisitions unnecessary. Hypothesis: We hypothetized that quantification of aortic valve calcification of VNC/ VNI series derived from CTA scans is feasable and correlates with calcium scores of TNC series. Methods: 45 consecutive patients underwent pre TAVR CT on a novel PCD-CT (NAEOTOM Alpha, Siemens Healthineers, Erlangen, Germany) comprising a non-contrast CT of the heart, followed by a CTA of the heart, aorta, and iliac arteries. VNC series were derived from CTA acquisitions and two readers independently quantified aortic valve calcium scores (Agaston score) and calcium volumes on VNC-, VNI- and TNC-series. Results: A total of 41 patients (41.46% female) were included in the study. In comparison with aortic valve calcium scores and volume scores derived from TNC series (i.e., 2800[2075-3681] vs. 2206[1645-2894] mm3), those derived from VNC (i.e., 752[390-1357] vs. 653.3[319.5-1052.3] mm3) and VNI (i.e., 1986[1270-3278] vs. 1515[971-2480] mm3) series were consistently lower but correlation was excellent for both, i.e., calcium and volume score, respectively (r’s: 0.96 and 0.96 for VNC; r’s: 0.92 and 0.91 for VNI, p&lt; 0.05). Conclusions: Our initial patient experience with TAVR planning CT on a novel PCD-CT showed signficant correlation of aortic valve calcium scores and volumes derived from VNC and VNI series, as compared with those derived from TNC series, thus rendering non-contrast acquisitions for TAVR planning redundant.
Abstract 14974: Diabetic Cardiomyopathy is Associated With Worsening of Quality of Life Long Before the Development of Overt Heart Failure: Lessons From the Baseline Analysis of the Arise-Hf Study
Authors: Alessia Urbinati, Riccardo Perfetti, Stella Wang, Sariah Persaud, Shoshana Shendelman, James L Januzzi
Journal: Circulation (2022)

Introduction: Diabetic Cardiomyopathy (DbCM) is a form of HF occurring in the absence of other causes of cardiac dysfunction such as hypertension, CAD, or valvular diseases in individuals with diabetes. The ARISE-HF study is designed to investigate the efficacy of AT-001, a novel aldose reductase inhibitor, in preventing the worsening of functional capacity in patients with DbCM. Hypothesis: The impact of DbCM on quality of life is greater than previously recognized, as patients with DbCM often adopt lifestyle changes to mitigate the impact of early symptoms. The hypothesis of the present study is that avoidance of physical activities in patients with DbCM may mask the clinical presentation of structural and functional myocardial changes that have occurred. Methods: The objective of the study was to investigate the physical activity levels in individuals with DbCM. We included patients with T2DM, age ≥60 years (or age ≥40 to &lt;60 years with duration of diabetes ≥10 years or eGFR &lt;60 mL/min/1.73 m 2 ), LVEF ≥45% in the presence of either elevated NTproBNP levels or elevated hs-cTn or echocardiographic abnormalities. Patients enrolled in the study had an impaired functional capacity measured as peak VO 2 &lt; 75% of predicted normal. Patients completed the Physical Activity Scale (PASE) questionnaire, a validated test designed to measure the amount of physical activity carried out during the prior week. Exclusion criteria included prior diagnosis of overt HF, history of CVD leading to cardiac dysfunction, elevated BP levels, and uncontrolled 2TDM (HbA1c&gt;8.5%). Results: We evaluated 363 patients (mean age 67.5 + 7.1 years, 47% female, BMI 30.3 + 4.6, NTproBNP 113.4 + 252.7 pg/mL, and HbA1c 7.0 + 0.8%) with diagnosis of DbCM. PASE score (mean 157.9 + 94) was indicative of reduced physical activity and was associated (p&lt;0.001) with peak VO 2 uptake (r= 0.31), underscoring the relationship between functional capacity and physical activity level. Conclusions: DbCM is a form of HF leading to decreased cardiac functional capacity. Many patients with DbCM have reduced their daily physical activities to mitigate the presentation of symptoms of fatigue; however, their quality of life is significantly affected by the disease even before the progression to overt HF.
Abstract 14982: Use of Electronic Health Records to Develop an Actionable Taxonomy of Patients With Persistent Hypertension
Authors: Yuan Lu, Cindy Hu, Hazar Khidir, Cesar Caraballo, Shiwani Mahajan, Erica S Spatz, Leslie Curry, Harlan M Krumholz
Journal: Circulation (2022)

Introduction: Digital transformation of medical data present opportunities for novel approaches to manage patients with persistent hypertension (HTN). Methods: This qualitative study was a thematic analysis of clinician notes in the electronic health records of patients in the Yale New Haven Health System. Eligible patients were 18 to 85 years and had blood pressure &gt;=160/100 mmHg at 5 or more consecutive outpatient visits between 1/1/2013 and 12/31/2018. 4,828 patients met criteria. We used conventional qualitative content analysis to develop a pragmatic framework of themes that distinguishes patients with persistent hypertension by their contributing factors. A random sample of 116 records were reviewed and analyzed when no new concepts emerge from analyses of subsequent data. Results: Of 116 patients, mean age was 64.5 (SD, 13.2) years; 55 % were female; 66 %, 21%, and 9% were White, Black, and Hispanic. The three themes emerged: (1) non-response to treatment, where patients were highly medically complex and biological resistance or secondary causes of HTN were significant components of their persistent HTN; (2) non-intensification of treatment, where issues such as provider specialty purview, competing medical priorities, patient preference, and concerns of white coat HTN contributed to treatment plans not being adjusted; (3) non-implementation of treatment plan, where varied concerns including a disconnect in patient education, difficulty obtaining medications, psychosocial barriers, or medication in tolerance caused appropriately escalated treatment plans to not be enacted. Conclusions: Our thematic analysis of patients’ medical records provides insights into actionable factors contributing to persistent HTN. These findings lay a foundation for designing digital tools for health systems to rapidly identify people with persistent HTN and connect them with targeted interventions at scale.